Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles

Mark E. Davis, Jonathan E. Zuckerman, Chung Hang J. Choi, David Seligson, Anthony Tolcher, Christopher A. Alabi, Yun Yen, Jeremy D. Heidel, Antoni Ribas

Research output: Contribution to journalArticle

1703 Citations (Scopus)

Abstract

Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

Original languageEnglish
Pages (from-to)1067-1070
Number of pages4
JournalNature
Volume464
Issue number7291
DOIs
Publication statusPublished - Apr 15 2010
Externally publishedYes

Fingerprint

RNA Interference
Nanoparticles
Small Interfering RNA
Messenger RNA
Double-Stranded RNA
Clinical Trials, Phase I
Caenorhabditis elegans
Therapeutics
Base Pairing
Interferons
Melanoma
Neoplasms
Proteins
Biopsy
Genes

ASJC Scopus subject areas

  • General

Cite this

Davis, M. E., Zuckerman, J. E., Choi, C. H. J., Seligson, D., Tolcher, A., Alabi, C. A., ... Ribas, A. (2010). Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature, 464(7291), 1067-1070. https://doi.org/10.1038/nature08956

Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. / Davis, Mark E.; Zuckerman, Jonathan E.; Choi, Chung Hang J.; Seligson, David; Tolcher, Anthony; Alabi, Christopher A.; Yen, Yun; Heidel, Jeremy D.; Ribas, Antoni.

In: Nature, Vol. 464, No. 7291, 15.04.2010, p. 1067-1070.

Research output: Contribution to journalArticle

Davis, ME, Zuckerman, JE, Choi, CHJ, Seligson, D, Tolcher, A, Alabi, CA, Yen, Y, Heidel, JD & Ribas, A 2010, 'Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles', Nature, vol. 464, no. 7291, pp. 1067-1070. https://doi.org/10.1038/nature08956
Davis ME, Zuckerman JE, Choi CHJ, Seligson D, Tolcher A, Alabi CA et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010 Apr 15;464(7291):1067-1070. https://doi.org/10.1038/nature08956
Davis, Mark E. ; Zuckerman, Jonathan E. ; Choi, Chung Hang J. ; Seligson, David ; Tolcher, Anthony ; Alabi, Christopher A. ; Yen, Yun ; Heidel, Jeremy D. ; Ribas, Antoni. / Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. In: Nature. 2010 ; Vol. 464, No. 7291. pp. 1067-1070.
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